Preparation of tert-alkyl azides from tertiary alcohols by way of benzoquinone-mediated oxidation-reduction condensation

Article abstract of DOI:10.1246/cl.2006.1432

A novel method for the preparation of alkyl azides from alcohols by way of oxidation-reduction condensation is described. According to this reaction, the sterically hindered tert-alkyl phosphinites that are prepared from the corresponding alcohols are con

Full text of DOI:10.1246/cl.2006.1432

1432
Chemistry Letters Vol.35, No.12 (2006)
Preparation of tert-Alkyl Azides from Tertiary Alcohols
by Way of Benzoquinone-mediated Oxidation–Reduction Condensation
Kiichi Kuroda,1 Nobuya Kaneko,2 Yujiro Hayashi,Ã1 and Teruaki MukaiyamaÃ2;3
1Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601
2Center for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
3Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received October 12, 2006; CL-061198; E-mail: mukaiyam@abeam.ocn.ne.jp)
A novel method for the preparation of alkyl azides from
alcohols by way of oxidation–reduction condensation is describ-
ed. According to this reaction, the sterically hindered tert-alkyl
phosphinites that are prepared from the corresponding alcohols
are converted into tert-alkyl azides with almost complete inver-
sions of their stereochemistries. On treatment with LiAlH4 the
obtained alkyl azides are then successfully reduced to afford
the corresponding amines in good yields, thus, a versatile meth-
od for the preparation of chiral amines from the corresponding
chiral alcohols was established.
R
R
O
O
O
O
OPPh2
O
Ph2P
R1
R3
TMS N3
R1
+ TMSN3
R2
1
R3
R2
A
R
R2
R3
O
OTMS
O
Ph2P
R1
R1
R
Ph2P
O
+
B
O
OTMS
N3
R3
R2
2
N3
''
''
Inversion
As the preparation of azides1 from alcohols by nucleophilic
substitution with an azide anion is noted a useful reaction for
introducing an amino-group, many trials have been made during
the past decade. For instance, Mitsunobu-type azidation2 such
uses diphenyl phosphorazidate (DPPA)3 or zinc azide/bis-pyri-
dine complex4 are good examples of versatile methods for the
conversion of alcohols into the corresponding azides. It is known
that the nucleophilic substitution proceeded via SN2 manner,
therefore, chiral secondary alkyl azides were formed from the
corresponding chiral secondary alcohols with complete inver-
sion of their stereochemistries. Although these methods have
widely been applied to the primary and secondary alcohols, there
are few reports on the sterically hindered ones to convert into the
corresponding azides.5
Scheme 1.
was expected to give the phosphinate derivative and the inverted
azide 2.
Based on these considerations, various 1,4-benzoquinone
derivatives were examined by taking condensation reaction of
tert-alkyl phosphinite 1a with trimethylsilyl azide (Table 1).
Phosphinite 1a gave the corresponding azide 2a in 56% yield
when 1,4-benzoquinone was employed. The reaction with 2,6-
disubstituted benzoquinone derivatives such as DMBQ and
DBBQ afforded the desired product in lower yield (Entries 2
and 3). Benzoquinones possessing one or two electron-donating
substituent(s) gave better results (Entries 4 and 5) while elec-
tron-withdrawing substituents retarded the reaction (Entries 7
and 8). Thus, it is noted that the result turned slightly better if
the reaction started at a lower temperature (Entry 6).
Recently, a new type of oxidation–reduction condensation
of carboxylic acids with alkyl phosphinites that were readily
prepared from the corresponding alcohols in the presence of
2,6-dimethyl-1,4-benzoquinone (DMBQ) was reported from
our laboratory,6 where almost complete stereochemical inver-
sion was observed even in the case of bulky tert-alkyl phosphin-
ites. It was also reported that a C–N bond forming reaction of
alkyl phosphinites with phthalimide was carried out by using
2,6-di-tert-butyl-1,4-benzoquinone (DBBQ).7 In the cases of
tert-alkyl phosphinites, however, the yield of the corresponding
N-alkyl phthalimides was poor. It is therefore desired to develop
a new and efficient method for the stereospecific conversion of
tert-alkyl alcohols into the corresponding amine derivatives.
In order to perform this process successfully, the following
oxidation–reduction condensation reaction by using benzoqui-
none derivatives and trimethylsilyl azide (TMSN3) as an azide
source was considered (Scheme 1). Reaction of alkyl phosphin-
ite 1 with a benzoquinone derivative was supposed to lead to the
formation of a zwitterionic intermediate A and subsequent O-
silylation with trimethylsilyl azide would result in the formation
of intermediate B and azide anion (N3À). Following nucleophilic
Next, the molar ratio of 1a, methoxybenzoquinone (MBQ)
and TMSN3 was examined, and the results are summarized
in Table 2. As the amount of TMSN3 increased, the yields of
Table 1. Effect of quinone derivatives on azidation of 1a
TMSN3 (2.4 equiv.)
Quinone (1.1 equiv.)
OPPh2
N3
Ph
Ph
CHCl3
0 °C to rt, 3 h
1a
2a
Entry
Quinone
Yield/%
R
1
2
3
4
R = H
56
R = Me
R = t-Bu
37
O
O
O
31a
57
R = OMe
R
OMe
5
58
O
6
7
8
63b
<7
Fluoranilc
DDQ
N. D.
aThe reaction was carried out for 17 h. bThe reaction temperature was
À45 ꢀC to room temperature. cTetrafluoro-1,4-benzoquinone.
À
attack of N3 on the phosphonium intermediate in SN2 manner
Copyright ꢀ 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.12 (2006)
1433
Table 2. Optimaization of reaction condition
Et N3
Et NH2
LiAlH4 (4.0 equiv.)
ether, rt
OMe
Ph
Ph
2f
3
84%
O
O (MBQ)
TMSN3
OPPh2
N3
Ph
Ph
Scheme 2.
CHCl3, 3 h
−45 °C to rt
1a
2a
good yields (Entries 2–4) while the reaction of benzylic phos-
phinite 1e or phosphinite having ester part (1g) gave the product
in moderate yields (Entries 5 and 6). It is noteworthy that the in-
verted products 2f were obtained with almost complete inversion
of stereochemistry when the chiral phosphinite 1f was employed
as a substrate.
This reaction proceeded as presumed at the beginning
(Scheme 1). The effect of the substituent of quinone derivatives
on the reaction is considered as follows: since O-silylation of the
intermediate A in Scheme 1 is irreversible and is playing an
important role in carrying out this transformation, an electron-
donating substituent of the quinone derivative enhances the
nucleophilicity of the intermediate A.
Since the chiral azide 2f was converted to the chiral amine
3 in good yield when 2f was treated with lithium aluminum
hydride in ether (Scheme 2), a concise method for the prepara-
tion of chiral amines from the corresponding alcohols was estab-
lished.
Thus, it is noted that tert-alkyl azides are synthesized under
neutral conditions by treating tert-alkyl phosphinites with
TMSN3 and MBQ. Chiral tert-alkyl azides were formed from
the corresponding chiral tert-alcohols with almost complete
inversion of configuration.
Entry 1a (equiv.) TMSN3 (equiv.) MBQ (equiv.)
Yield/%
1
2
3
4
5
6
7
1.0
1.0
1.0
1.0
1.0
1.0
1.6
1.8
2.4
3.0
5.0
2.4
2.4
1.0
1.1
1.1
1.1
1.1
1.1
1.1
1.6
56
63
60
65
53a
20b
90c
aMBQ was slowly added to the reaction mixture for 1 h at room tempera-
ture. b1a was slowly added to the reaction mixture for 3.5 h. cYield based
on TMSN3.
2a became slightly better (Entries 1–4). It is noted that there
were formed substantial amounts of the dehydrated alkenes,
4-phenyl-2-methylbut-2-ene and 4-phenyl-2-methylbut-1-ene,
under these conditions. Further, slow addition of either MBQ
(Entry 5) or TMSN3 (Entry 6) was examined so as to suppress
the formation of these alkenes. However, no substantial effect
on the formation of dehydrated alkenes was observed irrespec-
tive of the rates of addition: i.e. 2a was obtained in 53 and
20% yields, respectively. Then, 2a was finally obtained in
90% yield when 1.6 molar amount of 1a was used (Entry 7).
Next, the reactions of several secondary and tertiary alkyl
phosphinites were examined under the optimized conditions8
(Table 3): the secondary phosphinite 1b afforded the azide in
high yield (Entry 1). Tertiary alkyl phosphinites 1c, 1d, and 1f
were succsessfully converted into the corresponding azides in
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan. K.K. was
granted a Research Fellowship of the Japan Society for the
Promotion of Science for Young Scientist.
Table 3. Generality of the azidation by TMSN3
R1 OPPh2
R1 N3
MBQ (1.6 equiv.)
TMSN3
+
References and Notes
1
R2
R3
R2 R3
CHCl3
For a review for organic azides, see: S. Brase, C. Gil, K. Knepper, V.
¨
Zimmermann, Angew. Chem. Int. Ed. 2005, 44, 5188.
(1.0 equiv.)
−45 °C to rt
2
1 (1.6 equiv.)
2
For a review for Mitsunobu reaction, see: D. L. Hughes, in Organic
Reactions, ed. by L. A. Paquette, Wiley, New York, 1992, Vol. 42,
p. 335.
A. S. Thompson, G. R. Humphrey, A. M. DeMarco, D. J. Mathre,
E. J. J. Grabowski, J. Org. Chem. 1993, 58, 5886.
M. C. Viaud, P. Rollin, Synthesis 1990, 130.
a) A. Hassner, R. Fibiger, D. Andisik, J. Org. Chem. 1984, 49, 4237. b)
Recent example of preparation of tert-alkyl azides via Markovnikov
addition of an azide anion, see: J. Waser, B. Gaspar, H. Nambu,
E. M. Carreira, J. Am. Chem. Soc. 2006, 128, 11693.
a) T. Mukaiyama, T. Shintou, K. Fukumoto, J. Am. Chem. Soc. 2003,
125, 10538. b) T. Shintou, W. Kikuchi, T. Mukaiyama, Bull. Chem.
Soc. Jpn. 2004, 77, 1569.
For the preparation of N-alkyl phthalimides, see: a) T. Mukaiyama,
H. Aoki, Chem. Lett. 2005, 34, 142. For other C–N bond-forming
reactions from alkyl phosphinites, see: b) H. Aoki, K. Kuroda, T.
Mukaiyama, Chem. Lett. 2005, 34, 1266. c) T. Mukaiyama, K. Kuroda,
H. Aoki, Chem. Lett. 2005, 34, 1644. d) H. Aoki, T. Mukaiyama,
Chem. Lett. 2006, 35, 456.
Typical experimental procedure for the preparation of 2f is shown in
the following; to a stirred solution of 1f (232 mg, 0.64 mmol) in dry
CHCl3 (1.28 mL) were added 2-methoxy-1,4-benzoquinone (88.4 mg,
0.64 mmol) followed by trimethylsilyl azide (54.6 mL, 0.40 mmol)
at À45 ꢀC under argon atmosphere. The reaction mixture was allowed
to warm to room temperature and was stirred for 3 h. The reaction
mixture was directly purified by preparative TLC to afford 2f (67.8
mg, 83%).
Entry
1
Phosphinite
OPPh2
Yield/% Inversionf/%
92a
67b
3
rac-1b


Ph
4
5
OPPh2
2
3
4
1c
TBDPSO
Ph
79b
6
7
1d

Ph2PO
Et OPPh2
83b,c,d
57b,c,e
47a
1f (80% ee)
94
Ph
Et OPPh2
Ph
Ph OPPh2
MeO2C
5
6
1e (98% ee)
rac-1g
60
8

a1.0 equiv. of 1, 2.4 equiv. of TMSN3, and 1.1 equiv. of MBQ was used.
bYield was based on TMSN3. cThe ratio of enantiomer was determined
by HPLC analysis after reducing the azide to amine with LiAlH4. dThe de-
sired product was obtained in 75% ee. eThe desired product was obtained in
f
59% ee. Inversion (%) was defined as (% ee of 2)/(% ee of SM).
Published on the web (Advance View) November 25, 2006; doi:10.1246/cl.2006.1432